Scintigraphy
There is a substantial body of evidence that supports the use of ischemia imaging as a clinically relevant end point. This is particularly true of the nuclear medicine literature. A meta analysis of single-photon emission CT (SPECT) imaging, which included 69,655 patients referred for risk stratification, concluded that the presence of a moderate or severe perfusion defect was associated with an annual hard event rate of 5.9%, while a normal SPECT scan was associated with an annual risk of death or myocardial infarction (MI) of only 0.85%, a rate which is comparable to that of the general population [
7]. Similarly, an abnormal perfusion scan using rubidium positron emission tomography in patients with known or suspected CAD is associated with an annual risk of death of 4.3%, while a normal study is associated with an annual mortality rate of 0.9% [
8].
A general limitation of all perfusion techniques may arise from the presence of microvascular disease in diabetes, hypertension, and hypercholesterolemia. Microvascular disease is hypothesized to result in impaired perfusion in the absence of significant epicardial stenosis. This is thought to partially explain (the other reason being the low incidence of disease in the study population) why SPECT’s specificity is never found to be much higher than 75% to 80%. It is of interest that this lower specificity is not reflected in worsened prognostic power, suggesting that microvascular disease remains an important prognostic determinant.
Cardiac MRI
While nuclear perfusion imaging techniques are well established, they are increasingly compromised by concerns about radioactivity as well as more recent concerns surrounding isotope supply problems. Fortunately, the utility of stress perfusion CMR as an evidence-based diagnostic technique is also improving. MR-IMPACT was a multicenter head-to-head comparison of stress perfusion CMR and nuclear perfusion imaging that found the two techniques approximately equivalent in CAD detection [
9•]. This study was an important contribution to the field, as it provided strong evidence in support of CMR-based perfusion imaging. A recent meta analysis of the diagnostic performance of stress perfusion CMR which included 2,125 patients enrolled in 26 studies, reported an overall sensitivity of 89% and a specificity of 80% [
10••] of CMR stress perfusion when compared to the gold standard of coronary angiography. As discussed above, the relatively low specificity of CMR perfusion protocols is argued to be in part due to its sensitivity in identifying microvascular coronary disease which is not associated with epicardial stenosis [
11].
The prognostic evidence supporting stress perfusion CMR is more limited than the diagnostic characterization of the test, but is increasing. Jahnke et al. [
12] performed stress perfusion CMR studies on 513 patients with known or suspected CAD. During a median follow-up of 2.3 years, a positive scan was associated with a hazard ratio of 12.5 (CI = 3.6–43) for cardiac events [
12]. A recent study of 103 patients presenting to the emergency department with low-risk chest pain demonstrated that a normal adenosine CMR stress perfusion study was associated with no subsequent events over a mean follow-up of 277 days in this population [
13].
A significant issue with CMR stress perfusion imaging is the difficulty in obtaining adequate first-pass perfusion images in the transit time available. A novel solution to this problem has recently been presented in animal model work by Spuentrup et al. [
14]. They have identified a gadolinium-containing contrast agent with a high affinity for myocardial collagen. This agent allows CMR imaging to occur up to an hour after contrast injection while still retaining differential distribution of the contrast agent between normal and ischemic myocardium.
While CMR appears to be capable of replicating the subjective perfusion findings of the nuclear techniques, without the risks associated with radioactive tracers, CMR is capable of much more objective results in the determination of myocardial ischemia.
The capacity of CMR to quantitate myocardial blood flow has been elegantly demonstrated by Kurita et al. [
15•], who compared myocardial blood flow at stress and rest in normal and stenotic coronary arteries using both Doppler flow wires and with quantitative first-pass perfusion imaging of the regional myocardium. Their results showed a strong correlation between the two techniques and determined that quantitative first-pass stress perfusion CMR was capable of identifying physiologically relevant reduction in blood flow with a sensitivity of 88% and a specificity of 90% when compared to the flow wire as gold standard.
More recently, a comparison of fractional flow reserve (FFR), as determined by flow wire, to stress myocardial perfusion imaging has been performed in 103 patients with suspected angina [
16]. In this study, FFR was recorded in all patents’ major epicardial coronary arteries, and stress perfusion CMR was also performed. Myocardial perfusion scans identified perfusion defects in 121 of 300 coronary artery segments, of which 110 were likely subtended by vessels that had an FFR < 0.75 (indicating likely ischemia downstream). A total of 168 of 179 normally perfused segments had an FFR > 0.75. The sensitivity and specificity of stress perfusion CMR for the detection of functionally significant coronary heart disease were 91% and 94%, respectively, with positive and negative predictive values of 91% and 94% in this study.
The utility of quantifying perfusion CMR for research purposes is clear; however, given the time and effort required to produce these results, it has become standard practice in clinical settings to assess myocardial perfusion images subjectively. However, quantitative perfusion imaging by CMR does offer some clinical advantages over subjective evaluation. Perfusion reserve quantitation is capable of differentiating moderate from severe stenoses in patients. Quantitative techniques have also been shown to differentiate triple-vessel from single-vessel CAD, whereas this is difficult by subjective assessment [
17••]. This has important implications for assessment of prognosis, and adoption of quantitative methods in CMR perfusion imaging will need to be considered as stress perfusion CMR becomes a more widespread modality in routine clinical assessment.
In addition to the ability of CMR to provide quantitative information about myocardial perfusion, it offers well-established and robust imaging of previous myocardial infarction [
18,
19]. The combination of stress perfusion imaging and infarct visualization has been used to characterize the differences in appearance of ST elevation and non-ST elevation MI that may underlie the divergent natural histories of these injuries [
20]. Whether the combination of infarct imaging by late enhancement combined with stress perfusion imaging provides complementary prognostic information in assessing cardiovascular risk has long been of interest [
21•]. Data have recently become available addressing this question: 254 patients who were referred for assessment of symptomatic ischemia were imaged using both techniques and subsequently followed for a median of 17 months, with the primary end point being a composite of death and MI. Both the presence of infarct and reversible perfusion defects were associated with a threefold increase in cardiac death or acute MI (death/MI) when adjusted for each other and for the effects of patient age and gender (adjusted hazard ratio, 3.31;
P < 0.02; and hazard ratio, 3.43;
P < 0.01, respectively). In patients without a history of MI who had negative perfusion scan, infarct presence was associated with an 11-fold hazard increase in death/MI. Patients with neither perfusion defects nor infarct had a 98.1% negative annual event rate for death/MI. For association with major adverse cardiac events, stress perfusion imaging was the strongest multivariable variable (hazard ratio, 10.92;
P < 0.0001). Although further follow-up with greater patient numbers is required, it appears that the easily accomplished combination of these two techniques in one scanning session is likely to provide a powerful prognostic tool.